New Insights on Drug Retinopathy and Enhanced-Depth Imaging

The 52nd annual Walter Wright Ophthalmology and Vision Sciences Symposium offers the latest in ophthalmic research.

New Insights in Drug Retinopathy and Enhanced-Depth Imaging

The 52nd annual Walter Wright Ophthalmology and Vision Sciences Symposium offers the latest in ophthalmic research.

Louise Gagnon, Contributing Editor

The University of Toronto’s Department of Ophthalmology and Vision Sciences organized and hosted the 52nd annual Walter Wright Ophthalmology and Vision Sciences Symposium, which took place November 23 and 24 in Toronto. The annual event is named for renowned Canadian ophthalmologist Walter Wright, MD, who pioneered the use of leg muscle grafts to treat ptosis and, in the 1940s, instituted Canada’s first training program for ophthalmologists.

Dubbed “The Good, the Bad, and the Blurry,” this year’s symposium consisted of six sections on topics ranging from health-care policy and practice management to medical retina, our focus in this recap.


One of the most common systemic drugs that ophthalmolgists encounter as a source of ocular toxicity is tamoxifen, an antiestrogen therapy used to treat breast cancer, according to David R. Chow, MD, FRCSC, a vitreoretinal surgeon at St. Michael’s Hospital and assistant professor at the University of Toronto.

Dr. Chow showed an image of crystalline retinopathy (Figure 1), an example of a toxicity that can develop as a result of exposure to tamoxifen. He noted that a growing body of literature is pointing to the use of optical coherence tomography for the early detection of tamoxifen retinopathy (Figure 2).

The risk of ocular toxicity exists in 1% to 2% of patients on standard tamoxifen dosing, Dr. Chow said. Patients at highest risk for tamoxifen-induced ocular toxicity are women who have been on the therapy for more than one year and are taking a cumulative daily dose exceeding 100 mg, he noted.


Figure 1. Crystalline retinopathy can develop as a result of exposure to tamoxifen.


Figure 2. A growing body of literature is pointing to the use of OCT for the early detection of tamoxifen retinopathy.

A subgroup of patients who present with crystalline retinopathy go on to develop cystoid macular edema, Dr. Chow said. “The evolving literature is reinforcing the value of OCT, particularly for early detection,” he said. Spectral-domain OCT can be of particular value as a screening tool, Dr. Chow noted.


Figure 3. The presence of microcystoid foveal changes is an indication to discontinue tamoxifen.

The decision to allow a patient to continue tamoxifen depends on the presentation. The development of actual crystals is likely not associated with vision loss, so cessation is not required. Any associated vision loss that ensues is an indication to discontinue therapy, Dr. Chow said. The presence of microcystoid foveal changes on OCT and significant color vision loss are both indications to cease tamoxifen (Figure 3) therapy, he added.

Other Common Drug Toxicities

Macrodantin, which is prescribed to treat urinary tract infections, can produce crystalline features, and patients can experience severe burning, itching, and tearing, as well as muscle palsy and pseudotumor cerebri (Figure 4).

A presentation of a bull’s-eye maculopathy (Figure 5), resulting from the use of chloroquine or hydroxychloroquine, is an example of a case that is sent for consultation to ophthalmologists’ offices, Dr. Chow said.

“We all know chloroquine is used for malaria and is still prominently used by rheumatologists for autoimmune conditions like lupus and rheumatoid arthritis,” Dr. Chow said, noting that the toxicity risk is far more common with chloroquine than its analogue hydroxychloroquine (Plaquenil), with the latter agent more commonly used in North America.

Recent North American data show the rate of toxicity with Plaquenil in the first five years of therapy to be about one in 1,000 patients, increasing to 1% after five years, with an exponential rise after the seven-year mark (Figure 6). “The evolving literature on Plaquenil suggests the risk is mainly related to total dose,” Dr. Chow said.

Despite discontinuation of Plaquenil, the pathology may still progress, for the drug is bound to melanin and exuding toxicity, Dr. Chow said.

The American Academy of Ophthalmology released revised screening guidelines for chloroquine and hydroxychloroquine last year, calling for a baseline ophthalmic exam, a form of automated perimetry, and one of SD-OCT, multifocal electroretinography, or fundus autofluorescence.


Figure 4. Macrodantin can produce crystalline features, as well as burning, itching, and tearing.

Of note, Amsler grids have been removed from the recommendations as a screening tool, as they do not offer sufficient sensitivity and specificity.

Ocular Toxicity of ED Drugs

Patients who take the phosphodiesterase-5 (PDE5) inhibitor Viagra (sildenafil citrate) can present with a bluish tinge or photophobia, with the adverse ocular effects being dosedependent, Dr. Chow said.

“Why do we get ocular symptoms with Viagra?” he asked. “The bottom line is that there is a crossover effect where this drug blocks phosphodiesterase-6. If you look at our light or transduction cascade, phosphodiesterase-6 is critically involved in the pathway of the visual cycle.”

Screening is not thought to be necessary, given the lack of evidence of persistent retinal damage with Viagra. Still, accumulating literature has suggested a link between Viagra and central serous chorioretinopathy. One study showed after cessation of Viagra that six of eight patients who had CSC had improved vision.


Another presentation, on enhanced-depth imaging (EDI) demonstrated that ophthalmic diseases that feature thicker choroids, such as AMD, may be treated in the near future with Viagra and similar drugs that affect choroidal thickness.

“Viagra has been proved in prospective studies to make the choroid thicker by relaxing the smooth muscle,” explained Deepa Yoganathan, MD, FRCSC, DABO, clinical assistant professor and retina services director at the State University at New York, Buffalo. “It is not just a fun fact,” she said. “It may actually have therapeutic potential by increasing choroid thickness in diseases that have thinner choroids.”


Figure 5. Bull’s eye maculopathy can result from treatment with antimalarials.


Figure 6. Plaquenil retinopathy can pose a threat years after discontinuation.

In discussing advances in OCT, Dr. Yoganathan noted one prospective study that found a statistically significant difference in choroidal thickness, using EDI spectral-domain OCT, from baseline to one hour and three hours after taking a phosphodiesterase-5 inhibitor (Figure 7).

Dr. Yoganathan displayed an EDI image of a retina and noted that the outline of the sclera with the choroid was much more visible than it would be in an image for which EDI was not performed (Figure 8).

“The way this works is that you are increasing the signal-to-noise ratio by image averaging,” said Dr. Yoganathan. “For Heidelberg, they average about 100 scans per line with the help of eye tracking. That permits us to examine the choroidal circulation better. You can tell whether it’s diminished, which could mean atrophy or ischemia, or you can tell whether it’s engorged. It allows us determine choroidal thickness.”

Dr. Yoganathan cited a 2009 pilot study that introduced EDI-OCT in normal eyes to measure the choroid, which produced several interesting findings. The choroid was thickest underneath the fovea. The thickness reduced rapidly in the nasal direction, and increasing age was significantly linked to reduced choroidal thickness.


Figure 7. Choroidal thickness increased three hours after the patient took a PDE5 inhibitor.


Figure 8. Enhanced depth imaging offers better visualization of the outline of the sclera.


Dr. Yoganathan discussed the case of a 24-year-old obese Hispanic woman with Vogt-Koyanagi-Harada (VKH) disease, a condition where choroids were typically thicker, who presented with vision loss in both eyes (Figure 9). She was treated with 100 mg of prednisone, which was tapered slowly. A few months later, that patient presented with optic disc edema, which called the diagnosis into question.

“When you look at her choroidal thickness, it measured about 1 mm, or five times the normal thickness,” Dr. Yoganathan said. “Another pearl is that you can use choroidal thickness to help guide your tapering of prednisone. If you see that the choroid is responding to the prednisone and becoming thinner, this may be used to help to guide your taper regimen.”

Another benefit of EDI is that it can be a tool to distinguish between polypoidal choroidal vasculopathy and traditional wet AMD, said Dr. Yoganathan. Contrasting images, Dr. Yoganathan demonstrated patients with PCV were five times more likely to have thicker choroids (Figure 10). Choroidal thickness may explain why patients with polypoidal choroidal vasculopathy are more responsive to photodynamic therapy.


Figure 9. In this patient with Vogt-Koyanagi-Harada disease, a thicker choroid was seen.


Figure 10. Patients with polypoidal choroidal vasculopathy are five times more likely to have thicker choroids.

A published observation is that choroidal thickness is the most significant predictor of visual acuity in highly myopic eyes. Indeed, for every diopter of myopia, a patient loses 8.7 μm of thickness, and thinner choroids are at elevated risk for choroidal neovascularization, information that is of value in terms of screening, Dr. Yoganathan said.

Thinner choroids are also found in diabetes-related eye disease (Figure 11), Dr. Yoganathan said. Many ongoing studies have shown the choroids in cystoid macular edema and treated proliferative diabetic retinopathy are thinner than normal, she noted.

Still another application for EDI is in ocular oncology. Dr. Yoganathan pointed to retrospective research published by Carol Shields, MD. This research concluded that EDI allows clinicians to discern between choroidal nevi and melanoma through not only more accurate measurement of choroidal lesion height, but also with features more likely to be found in melanomas, such intraretinal fluid and shaggy photoreceptors.


Figure 11. Thinner choroids are seen in conditions related to diabetes.


Figure 12. Widefield OCT could also be helpful in determining the limitations of ocriplasmin for macular hole.


Dr. Yoganathan also noted wide-field montage OCT may aid in determining limitations to employing emerging therapies for macular hole and vitreomacular traction (Figure 12). “The physician and patient need to be aware of the adverse events,” she said. “There is a risk of tear and retinal detachment. It will be important to do a very good scleral-depressed exam beforehand to identify areas of weakness in the periphery. Wide-field OCT can also help us identify areas of retinoschisis.”


Retinal Physician will wrap up coverage of the 2012 Retinal Physician Symposium in the spring, in time for the next RP Symposium, June 5-8, 2013, in Las Vegas, NV. Keep an eye on the Events Calendar (page 76). RP